State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau 999078, China.
Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, China.
Nano Lett. 2021 May 12;21(9):3721-3730. doi: 10.1021/acs.nanolett.0c04772. Epub 2021 Apr 23.
Chemo-immunotherapy combination effect remains to be a great challenge due to the poor tumor penetration of therapeutic agents that resulted from condensed extracellular matrix (ECM), T cell-related immune escape, and thus the potential recurrence. Herein, a helix self-assembly camptothecin (CPT) prodrug with simultaneous physical and physiological tumor penetration was constructed to realize effective chemo-immunotherapy. Specifically, CPT was modified with arginine to self-assemble into nanofibers to physically improve tumor penetration. Two plasmids, shPD-L1 and Spam1 for expressing small hairpin RNA PD-L1 and hyaluronidase, respectively, were loaded to down-regulate tumor surface PD-L1 expression for converting anergic state of T cells into the tumor-reactive T cells and produce hyaluronidase to physiologically degrade ECM for further enhanced tumor penetration. Moreover, the degraded ECM could also increase immune cells' infiltration into tumor sites, which may exert a synergistic antitumor immunity combined with immune checkpoint inhibition. Such a nanomedicine could cause significant inhibition of primary, distant tumors, and effective prevention of tumor recurrence.
由于治疗药物由于细胞外基质（ECM）的凝聚、T 细胞相关免疫逃逸而导致的肿瘤穿透性差，化学免疫疗法的联合效果仍然是一个巨大的挑战，因此存在潜在的复发风险。在此，构建了一种具有同时物理和生理肿瘤穿透能力的螺旋自组装喜树碱（CPT）前药，以实现有效的化学免疫治疗。具体而言，将 CPT 用精氨酸修饰以自组装成纳米纤维，从而物理地提高肿瘤穿透性。两种质粒，shPD-L1 和 Spam1，分别用于表达小发夹 RNA PD-L1 和透明质酸酶，用于下调肿瘤表面 PD-L1 表达，将 T 细胞的无反应状态转化为对肿瘤有反应的 T 细胞，并产生透明质酸酶来生理降解 ECM，以进一步增强肿瘤穿透性。此外，降解的 ECM 还可以增加免疫细胞浸润到肿瘤部位，这可能与免疫检查点抑制相结合发挥协同抗肿瘤免疫作用。这种纳米药物可以显著抑制原发性、远处肿瘤，并有效预防肿瘤复发。
